Muscle-invasive Bladder Cancer
Conditions
Brief summary
This is a global Phase III, randomized, placebo-controlled, double-blind study designed to evaluate the efficacy and safety of adjuvant treatment with atezolizumab compared with placebo in participants with MIBC who are circulating tumour deoxyribonucleic acid (ctDNA) positive and are at high risk for recurrence following cystectomy.
Interventions
DEVICESignatera
Signatera will be used to evaluate whether ctDNA is detected during serial monitoring of peripheral blood samples for participants enrolled in surveillance. Participants with a ctDNA positive result will be screened for inclusion in the treatment phase. Participants who remain ctDNA negative at 12 months from the date of cystectomy will not be randomized to treatment and will enter surveillance follow-up.
DRUGAtezolizumab
ctDNA positive participants will receive 1680 mg IV, every 4 weeks (Q4W) on Day 1 of each 28-day cycle.
OTHERPlacebo
ctDNA positive participants will receive placebo IV, Q4W on Day 1 of each 28-day cycle
Sponsors
Hoffmann-La Roche
Natera, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Following the primary analysis, the Sponsor has been unblinded, and the investigators can now be unblinded upon request to guide treatment decisions.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion Criteria for the Surveillance Phase: * Histologically confirmed MIUC (also termed transitional cell carcinoma \[TCC\]) of the bladder * Tumor, nodes, and metastases (TNM) classification (based on American Joint Committee on Cancer \[AJCC\] Cancer Staging Manual, 8th Edition; Amin et al. 2016) at pathological examination of surgical resection specimen as follows: For participants treated with prior neoadjuvant chemotherapy (NAC): tumor stage of ypT2-4a or ypN+ and M0. For participants who have not received prior NAC: tumor stage of pT2-4a or pN+ and M0 * Surgical resection of MIUC of the bladder * Participants who have not received prior platinum-based NAC must be ineligible for cisplatin-based adjuvant chemotherapy, have refused it, or will not receive it based on physician's decision * ctDNA assay developed based on tumor tissue specimen and matched normal DNA from blood * Tumor programmed death ligand (PD-L1) expression per immunohistochemistry (IHC) that is evaluable by central testing of a representative tumor tissue specimen * Absence of residual disease and absence of metastasis, as confirmed by a negative baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan of the pelvis, abdomen, and chest no more than 4 weeks prior to enrollment * Full recovery from cystectomy and enrollment within 24 weeks following cystectomy. Minimum of 6 weeks must have elapsed from surgery Additional Inclusion Criteria for the Treatment Phase: * Blood for plasma ctDNA sample evaluated to be ctDNA positive, defined as the presence of two or more mutations out of the 16 mutations identified based on participant' whole exome sequencing (WES) evaluable (ctDNA assay designability) report * Absence of residual disease and absence of metastasis, as confirmed by a negative baseline CT or MRI scan of the pelvis, abdomen, and chest no more than 28 days prior to randomization, as assessed by the investigator and Independent Review Facility * Eastern cooperative oncology group (ECOG) performance status of ≤ 2 * Life expectancy ≥12 weeks * Adequate hematologic and end-organ function * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs
Exclusion criteria
General Medical
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| INV-assessed Disease-free Survival (DFS) | From randomization to the first occurrence of a DFS event (Up to 48.2 months) | INV-assessed DFS was defined as the time from randomization to the first occurrence of a DFS event, defined as any of the following: local (pelvic) recurrence of urothelial carcinoma (UC) (including soft tissue and regional lymph nodes); urinary tract recurrence of UC (including all pathological stages and grades); distant metastasis of UC; or death from any cause. Participants without an INV-assessed DFS event were censored at the last date the participant was assessed to be alive and recurrence-free as determined with radiographic evidence. Kaplan-Meier (KM) methodology was used to estimate the median DFS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization to death from any cause (Up to 48.2 months) | OS was defined as the time from randomization to death from any cause. Data for participants who did not die at the time of analysis were censored at the date last known to be alive. Data for participants who did not have post-baseline information were censored at the date of randomization. KM methodology was used to estimate the median OS. |
| Independent Review Facility (IRF)-Assessed DFS | From randomization to the first occurrence of a DFS event (Up to 48.2 months) | IRF-assessed DFS was defined as the time from randomization to the first occurrence of a DFS event, defined as any of the following: local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes); urinary tract recurrence of UC (including all pathological stages and grades); distant metastasis of UC; or death from any cause. Participants without an IRF-assessed DFS event were censored at the last date the participant was assessed to be alive and recurrence-free as determined with radiographic evidence. KM methodology was used to estimate the median DFS. |
| INV-assessed Disease-specific Survival (DSS) | From randomization to death from UC (Up to 48.2 months) | INV-assessed DSS was defined as the time from randomization to death from UC per investigator assessment of cause of death. Data for participants who did not die will be censored at the last date they were known to be alive. Data for participants who died from causes other than bladder cancer were censored at the date of death. KM methodology was used to estimate the median DSS. |
| INV-assessed Distant Metastasis-free Survival (DMFS) | From randomization to the first occurrence of a DMFS event (Up to 48.2 months) | INV-assessed DMFS was defined as the time from randomization to the first occurrence of a DMFS event, defined as diagnosis of distant (i.e., non-locoregional) metastasis or death from any cause. Data for participants without a DMFS event were censored at the last date the participant was assessed to be alive and free of distant metastasis. Data for participants with no post-baseline disease assessment were censored at the randomization date. KM methodology was used to estimate the median DMFS. |
| Time to Confirmed Deterioration (TTCD) in Physical Functioning, Role Functioning & Global Health Status/Quality of Life (GHS/QoL), Assessed by European Organisation for Research & Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) | Up to 11.8 months | TTCD of physical functioning (PF), role functioning (RF) \& health-related quality of life (HRQoL) was defined as time from randomization to first documented confirmed deterioration. Confirmed deterioration=participant's first ≥10-point score decrease from baseline on EORTC QLQ C30 PF, RF or GHS/QoL scale that must be held for ≤2 consecutive time points or followed by death due to cancer progression within 8 weeks from last patient-reported outcomes (PRO) assessment. EORTC QLQ-C30 has 30 questions assessing 5 aspects of participant functioning (physical, emotional, role, cognitive \& social), 3 symptom scales (fatigue, nausea \& vomiting \& pain), GHS/QoL \& 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea \& financial difficulties). Functioning items are scored on a 4-point scale (1=Not at All to 4=Very Much) \& GHS/QoL on a 7-point scale (1=very poor to 7=excellent). Scores are linearly transformed on a scale of 0 to 100. High score=better functioning/better QoL. |
| Percentage of Participants With ctDNA Clearance | Baseline, Day 1 of Cycles 3 or 5 (Cycle length = 28 days) | ctDNA clearance was defined as the percentage of participants who were ctDNA positive at baseline and ctDNA negative at Cycle 3, Day 1 or Cycle 5, Day 1. Percentages have been rounded off. |
| Number of Participants With Adverse Events (AEs) | From initiation of study treatment up to approximately 5 years | AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| Maximum Serum Concentration (Cmax) of Atezolizumab | 30 minutes post dose on Cycle 1 Day 1 (Cycle length = 28 days) | — |
| Minimum Serum Concentration (Cmin) of Atezolizumab | Pre-dose on Day 1 of Cycles 2, 3, 4, 8 and 12 (Cycle length = 28 days) | — |
| Number of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab | Up to 12.8 months | Participants who received atezolizumab were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following atezolizumab exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants with a positive post-baseline sample have been reported here. |
Countries
Argentina, Belgium, Brazil, China, Colombia, Czechia, France, Germany, Greece, Hong Kong, Ireland, Israel, Italy, Japan, Poland, Russia, Singapore, South Korea, Spain, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 761 participants with high-risk muscle-invasive bladder cancer (MIBC) who underwent radical cystectomy were enrolled in the surveillance phase of the study after confirming no radiographic evidence of residual disease. Patients were eligible regardless of whether they had received prior platinum-based neoadjuvant chemotherapy (NAC). Participants were enrolled at 157 investigative sites across 24 countries. The study is still ongoing.
Pre-assignment details
Participants enrolled in the Surveillance Phase who tested ctDNA positive and continued to have no evidence of radiographic disease were randomized into the Treatment Phase to receive either atezolizumab or placebo.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 117 Participants |
| Age, Categorical Between 18 and 65 years | 248 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 45 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 70 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 42 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 52 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) White | 430 Participants |
| Sex: Female, Male Female | 166 Participants |
| Sex: Female, Male Male | 387 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 761 | 36 / 83 | 60 / 167 |
| other Total, other adverse events | 0 / 0 | 54 / 83 | 107 / 165 |
| serious Total, serious adverse events | 0 / 0 | 17 / 83 | 44 / 165 |
Outcome results
None listed